SKCD in Early Relapsed/Refractory Multiple Myeloma

Inclusion Criteria

Candidates must satisfy all of the following inclusion criteria to be enrolled in the study:

• 1. Age: Age > 18 years, male or female.

• 2. Measurable Disease: Diagnosed with multiple myeloma according to the 2014 IMWG diagnostic criteria, with measurable disease at screening defined by at least one of the following:

  1. Serum M-protein level > 10 g/L (1.0 g/dL); OR
  2. 24-hour urine M-protein excretion > 200 mg/24 hours; OR
  3. In light chain multiple myeloma without measurable serum or urine M-protein: serum involved free light chain (FLC) > 100 mg/L (10 mg/dL) with an abnormal serum FLC kappa/lambda ratio (normal reference range: 0.26-1.65).

• 3. Disease Status & Life Expectancy: Patients with early relapsed or refractory multiple myeloma, with an anticipated life expectancy of >= 6 months.

• 4. Prior Therapy Lines: Must have received 1 to 3 prior systemic treatment lines. Induction therapy followed by autologous stem cell transplantation (ASCT) with or without maintenance therapy is counted as a single line of therapy. Participants must have received at least one regimen containing a proteasome inhibitor (e.g., bortezomib, ixazomib, carfilzomib) and/or an immunomodulatory drug (e.g., lenalidomide, pomalidomide; excluding thalidomide monotherapy), and demonstrated disease progression or relapse during or after such therapy (single-agent or combination). Prior anti-CD38 monoclonal antibody exposure is permitted but not mandatory. Radiotherapy, bisphosphonate therapy, or a single brief course of corticosteroids (equivalent dose not exceeding dexamethasone 20 mg/day for <= 4 days) are not counted as prior systemic treatment lines.

• 5. Documented Disease Progression: Documented evidence of progressive disease (PD) during or following the most recent anti-myeloma regimen based on IMWG consensus criteria. Progressive disease requires at least one of the following compared with the nadir value:

• An increase of >= 25% in serum M-protein (with an absolute increase of >= 5 g/L); or an absolute increase of >= 10 g/L if baseline serum M-protein was >= 50 g/L;

• An increase of >= 25% in 24-hour urine M-protein (with an absolute increase of >= 200 mg/24 h);

• In patients without measurable serum and urine M-protein, an increase of >= 25% in the difference between involved and uninvolved FLC levels (dFLC, with an absolute increase > 100 mg/L);

• In patients without measurable serum/urine M-protein and involved FLC, an increase of >= 25% in bone marrow plasma cell percentage (with an absolute increase of >= 10%);

• Development of new extramedullary plasmacytomas: an increase of >= 50% in the sum of the products of the perpendicular diameters (SPD) of > 1 existing measurable lesion compared to nadir, or an increase of >= 50% in the longest diameter of a pre-existing lesion >= 1 cm;

• When circulating plasma cells represent the only measurable parameter, an increase of > 50% in circulating plasma cells (with an absolute count of at least 200 cells/uL).

• 6. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2 at screening and prior to initiation of study treatment.

• 7. Organ and Laboratory Function: Adequate hematologic, hepatic, renal, and metabolic organ function prior to enrollment, satisfying:

• Hemoglobin >= 80 g/L (without red blood cell transfusions or erythropoietin within 7 days prior to laboratory assessment);

• Platelet count: > 75 x 10⁹/L in patients with < 50% bone marrow nucleated cells composed of plasma cells; > 50 x 10⁹/L in patients with >= 50% bone marrow plasma cells (without platelet transfusions or thrombopoietin receptor agonists within 7 days prior to assessment);

• Absolute Neutrophil Count (ANC) > 0.5 x 10⁹/L (growth factor support permitted, but G-CSF or GM-CSF must be discontinued for >= 7 days, and pegylated G-CSF for >= 14 days prior to assessment);

• Hepatic function: AST and ALT <= 2.5 x ULN; Total bilirubin <= 2.5 x ULN, except in patients with congenital hyperbilirubinemia such as Gilbert syndrome (in which direct bilirubin must be < 1.5 x ULN);

• Renal function: Estimated glomerular filtration rate (eGFR) > 30 mL/min, calculated using the Modification of Diet in Renal Disease (MDRD) equation or measured by 24-hour urinary creatinine clearance;

• Serum calcium: Albumin-corrected serum calcium <= 14 mg/dL (< 3.5 mmol/L) or ionized calcium <= 6.5 mg/dL.

• 8. Disease Subtype Definitions: Relapsed, refractory, or clinical relapse defined as follows:

• Relapsed Disease: Patients who initially achieved a response to prior therapy and subsequently developed confirmed disease progression per IMWG criteria > 60 days after therapy cessation.

• Refractory Disease: Patients who experienced disease progression per IMWG criteria during prior therapy or within < 60 days of discontinuing prior therapy, or had an M-protein increase of >= 25%.

• Clinical Relapse: Defined by >= 1 of the following: (1) Development of new bone lesions or soft-tissue plasmacytomas (excluding osteoporotic fractures); (2) Definite increase in the size of existing plasmacytomas or bone lesions (>= 50% increase in SPD of measurable lesions and absolute increase >= 1 cm); (3) Hypercalcemia (> 2.75 mmol/L); (4) Decrease in hemoglobin concentration >= 20 g/L (unrelated to therapy or non-MM causes); (5) Increase in serum creatinine >= 176.8 umol/L (2 mg/dL) from initiation of MM therapy, attributable to myeloma; (6) Hyperviscosity related to serum M-protein.

• 9. Informed Consent: Voluntary written informed consent signed by the patient or legally authorized representative.

Exclusion Criteria

Candidates meeting any of the following exclusion criteria shall be excluded from study participation:

• 1. Hypersensitivity: Known contraindication, life-threatening allergy, severe hypersensitivity, or intolerance to any study drug active ingredients or excipients.
• 2. Prior Antineoplastic Therapy Washout: Prior therapy washout requirements:
• Targeted therapy, epigenetic therapy, or investigational drug treatment within 21 days or > 5 elimination half-lives (whichever is shorter) prior to first study dose; or use of an invasive investigational medical device;
• Administration of an approved or emergency-use investigational vaccine (other than SARS-CoV-2 vaccines) within 4 weeks; administration of live attenuated vaccines within 4 weeks;
• Monoclonal antibody therapy within 21 days;
• Cytotoxic chemotherapy within 21 days;
• Proteasome inhibitor (PI) therapy within 14 days;
• Immunomodulatory drug (IMiD) therapy within 14 days;
• Radiotherapy within 14 days, or focal palliative radiotherapy within 7 days.
• 3. CNS Involvement: Known active central nervous system (CNS) involvement or clinical signs of meningeal myeloma. In suspected cases, brain MRI and lumbar puncture cytology must be negative.
• 4. Specific Hematologic Conditions: Diagnosis of plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), or primary light chain (AL) amyloidosis at screening.
• 5. Second Malignancies: Non-hematologic malignancy diagnosed within 3 years prior to enrollment (unless curatively treated), or presence of therapy-related myelodysplastic syndrome (t-MDS).
• 6. Cardiovascular Diseases: Cardiovascular diseases including:
• New York Heart Association (NYHA) Class III or IV congestive heart failure;
• Myocardial infarction or coronary artery bypass grafting (CABG) within 6 months prior to enrollment;
• Clinically significant ventricular arrhythmias, or history of unexplained syncope;
• History of severe non-ischemic cardiomyopathy.
• 7. Infectious & Pulmonary Diseases: Infectious, pulmonary, or neurologic conditions including:
• Uncontrolled hepatitis B virus infection (positive HBsAg or HBV-DNA): if infection status is indeterminate, HBV-DNA viral quantification must be performed. Active hepatitis C virus (HCV) infection, defined as positive HCV-RNA. Patients with a history of HCV antibody positivity must undergo HCV-RNA testing; patients with resolved chronic hepatitis C who completed antiviral therapy and maintained undetectable HCV-RNA for >= 12 weeks post-treatment are eligible;
• Chronic obstructive pulmonary disease (COPD) with FEV1 < 50% of predicted normal value;
• Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any type;
• Significant peripheral neuropathy at baseline (Grade 3, Grade 4, or Grade 2 with associated pain).
• 8. Major Surgery: Major surgery within 2 weeks prior to initiating study treatment, incomplete surgical recovery, or major elective surgery planned during the study treatment period or within 2 weeks following the last study dose.
• 9. Investigator Discretion: Any medical, psychiatric, or other condition that, in the opinion of the investigator, makes the patient unsuitable for trial participation.